An Overview of Ocular Herpetic Disease

Oral antivirals are the cornerstone of therapy for ocular herpetic disease, but careful diagnosis and judicious comanagement play essential roles as well.

By William B. Potter, O.D.

Release Date: MAy 2010

Expiration Date: MAY 31, 2013

Goal Statement:

Ocular herpes is a challenge for both the optometrist and the patient. Current licensure generally allows the optometrist to prescribe the full range of anti-herpetic agents, yet many cases remain unresolved and may require subspecialty care. This course explains how to identify and treat cases of ocular herpetic disease, and when to refer patients for further care.

Faculty/Editorial Board:

William B. Potter, O.D.

Credit Statement:

This course is COPE approved for 2 hours of CE credit. COPE ID is 28164-SD. Check with your local state licensing board to see if this counts toward your CE requirement for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Dr. Potter is on the speakers bureau for Alcon.

The presentation of ocular
herpes is a challenge for
both optometrists and
patients. Although current licensure generally allows
the optometrist to prescribe a full
range of anti-herpetic agents, many
cases remain unresolved and may
require subspecialty care.

The major herpes viruses that
cause ocular disease—simplex and
zoster—often cause ongoing immunologic reactions that outlive the
active infection. Other members of
the herpes family, such as Epstein Barr and cytomegalovirus, are less
frequent causes of ocular pathology. So, in this article, I’ll limit the
discussion to herpes simplex and
herpes zoster.

The Herpes Virus

We know herpes infections have
been recognized for many centuries,
from Hippocrates’ description of
skin lesions that “creep and crawl”
to Shakespeare’s reference to “blister
plagues.” More scientifically, Vidal
noted human-to-human transmission in 1893, and Lowenstein found
transmission in a laboratory setting
in 1919.1

Patients often misunderstand the
origins of herpes infections, assuming that it’s a sexually transmitted
disease. Because this is true in only
a minority of ocular cases, a good
history and proper counseling at
initial diagnosis can help overcome
this notion and reduce the patient’s
anxiety.

The herpes viruses are classified
as DNA viruses, meaning that their
genetic material is in the form of
DNA, which is double-stranded.
This is an important concept in
understanding the therapy for herpetic infection because both topical and oral agents rely on their anti-DNA transcription properties to
achieve effectiveness. Therapeutic
agents prevent the viral DNA from
being “read,” thereby stopping protein synthesis and replication.

The hallmark of the herpes virus
family is its ability to remain latent
in the sensory ganglia. The viral
genome, or genetic sequence, is
retained in an inactive form until
the host organism’s immune system
is weakened.2 While not all humans
manifest herpes infection, more
than 90% carry the latent virus.

An individual’s genetic makeup
and immunologic status, as well as
the strength of the infecting virus,
determine ongoing latency or active
infection. The nerve cell itself may
employ peptides and hormones that
keep the viral activity in check.2

Virus and Inflammation

The inflammatory phase of herpes
infections can be especially damaging and difficult to manage. This
may be explained by the concept of
molecular mimicry, where the herpes
virus causes coding of proteins that
are similar to those of normal tissue. For example, it is thought that
the herpes simplex virus has a coat
protein called UL6, which is similar to proteins found in the human
cornea. This presents an obvious
problem: As the human immune system becomes conditioned to attack
the offending virus, it will also tend
to attack normal tissue.2 When this
happens, white blood cells known
as CD4+ T cells are activated, which
release chemokines and Th1 cytokines, triggering a destructive inflammatory cascade.

Another possible source of inflammation in herpes simplex infection
is a viral protein known as glyco-protein K. This protein apparently
induces other white blood cells,
known as CD8+ T cells, to come to
the inflammatory site. CD8+ cells are
thought to be responsible for the corneal scarring that is so familiar to the
eye practitioner for its devastating
visual consequences.3

Identifying Ocular Herpes

Herpes simplex is the leading cause of infectious corneal blindness in the United States.4 In its epithelial form, dendritic keratitis is the most common presentation to the primary care optometrist. Confusion of these lesions with pseudodendrites is a common problem that can best be solved by remembering the two key features of the classic dendritic lesion: True dendritic lesions show arborization and terminal end bulbs.

Secondarily, the clinician can be tipped to the possibility of prior herpes infection if there exists unexplained corneal scarring, corneal hypoesthesia or iris atrophy. Pseudodendrites can be caused by contact lenses and their solutions, trauma, dry eye, and other infections, especially herpes zoster. A good history can be a key tool in differentiating such lesions.

Topical Treatment

We have a couple options for topical treatment of herpetic keratitis:

• Viroptic. Viroptic (trifluridine,
GlaxoSmithKline) is the cornerstone
of topical treatment for herpes simplex keratitis. It is given one drop
every two hours for one week in the
affected eye until the corneal epithelium is sufficiently healed. Further
treatment is then suggested at four
times daily for another week.

This drug interferes with viral
replication by blocking DNA transcription. It is very effective, though
toxicity is a significant risk. Increased
redness, pain, infiltrates and corneal
staining, despite improvement in the
dendritic lesion, suggest drug toxicity. Although the literature expresses
caution at treatment periods longer
than 21 days, we have seen toxicity
reactions to trifluridine in as early as
five to seven days.

• Vira-A. Another popular topical
drug, the ointment Vira-A (vidarabine, Monarch Pharmaceuticals),
was used in conjunction with Viroptic, but it has been off the market for
several years. Another topical antiviral, acyclovir, is used in Europe, but
does not have approval for herpes
simplex keratitis here in the United
States.

• Zirgan. In September 2009, the
FDA approved Zirgan (ganciclovir
gel 15%, Sirion Therapeutics) for
acute herpetic keratitis (dendritic
ulcers). European practitioners have
had access to ganciclovir ophthalmic
gel for more than 10 years. Its dosage is one drop five times daily until
resolution of the ulcer, then three
times daily for another seven days.
Research and clinical experience will
hopefully prove the effectiveness of
this product now that it is available
in the United States.

Oral Treatment

Oral Dosing for Herpes Simplex

If an oral agent is appropriate, a prescription for herpes simplex should be administered as follows:

Zovirax (acyclovir, GlaxoSmithKline) 400mg five times daily for seven to 10 days

Valtrex (valacylovir, GlaxoSmithKline) 500mg three times daily for seven to 10 days

Famvir (famciclovir, Novartis) 250mg three times daily for seven to 10 days.

Oral treatment for acute herpes
simplex keratitis, though not without controversy, has become common practice. (See “Oral Dosing
for Herpes Simplex,” right.) Such
treatment may at least reduce the
viral load in the ciliary ganglion and
associated nerves, even if there isn’t
a large effect in the corneal epithelium.

On the other hand, some researchers have suggested that an orals only
approach is clinically effective in the
absence of the potentially toxic topical drugs.5 Incontrovertible research
on this topic is lacking. Because
the cornea has no blood supply,
the orals only approach relies on
the knowledge that oral acyclovir
achieves supratherapeutic levels in
the precorneal tear film.6

Our treatment choice is to use topical trifluridine or the newer ganciclovir, with conservative monitoring,
as well as the oral agent. Hopefully,
a large sample study will vindicate
the orals only approach to herpes
simplex keratitis. We’ve had some
success with the no topicals method
in patients whose epithelium is
compromised by self-treatment with
over-the-counter agents or excessive
topical antibiotics. While acyclovir has been a
mainstay herpetic treatment for
years, we tend to prefer the newer
prodrug valacyclovir. Prodrugs
are compounds that are converted
to a more active form of the drug
once introduced into the patient’s
system. In this case, valacyclovir
is converted to acyclovir in the
patient’s intestine and liver, and
it achieves effective therapeutic
levels in the serum with a smaller
quantity of drug required. It is
then phosphorylated to its most
active form within virus infected
cells. Famciclovir is converted to
penciclovir upon ingestion and is
similarly phosphorylated within
infected cells.

While these drugs are not high
in systemic toxicity, patients
often have mild upset stomach or
headache upon starting treatment.
Reassure patients in advance
that these symptoms may occur,
and that they generally pass. As
always, take extra caution with
patients who have kidney or liver
dysfunction, or who are taking
multiple medications. Consultation with the patient’s internist is
always a wise approach.

Controversies in HSV Treatment

There are several myths that need to be debunked about herpes simplex treatment.

“Don’t treat the first episode.”

Although poorly referenced in the literature, some practitioners believe that it’s beneficial to defer treatment the first time a patient has an episode of systemic herpes simplex. The rationale is that the immune system mounts a better long-term response if it’s permitted to respond to the unchecked infection.

In interviewing local specialists in pediatric ophthalmology and infectious disease, I found that the no-treatment notion is disputed as dangerous because the possible manifestations of disseminated herpes outweigh the risk of a suppressed immune response. Appropriate antiviral treatment does not imply that the patient’s immune response will be underdeveloped.

“Don’t treat dry eye and herpes simultaneously.”

At least one study has reported favorable results when treating herpes simplex keratitis in patients who concurrently suffer from dry eye.9 The combination of punctal cautery and Restasis (cyclosporine, Allergan) therapy reduced the recurrence rate of herpes simplex stromal keratitis in a sample of 42 patients. This study is interesting because it suggests that dry eye is a stressor that may contribute to stromal keratitis in the herpes patient.

More importantly, it should prove reassuring that Restasis can indeed be used in patients who have suffered herpes simplex keratitis, albeit with close monitoring. Since its introduction, our practice has successfully prescribed Restasis for dry eye patients who have a history of herpes simplex keratitis, provided that there are no active epithelial lesions. However, we continue to respect Allergan’s comment that the product has not been studied for safety on these patients.

“Don’t treat herpetic eyes with topical steroids or you’ll make them worse.”

Traditional optometric teaching may have inadvertently discouraged proper usage in the early years of ocular therapeutic education. In addition, opposition to optometric drug laws had painted steroid use as inappropriate, with herpetic exacerbation as the feared endpoint.

However, topical steroid use is a required element in the treatment of several forms of ocular herpes simplex. Disciform keratitis and other stromal inflammations (to the viral coat proteins described earlier) will go unresolved without immunosuppression. Herpetic iritis is also treated with aggressive steroid use, including hourly prednisolone acetate and cycloplegia as cornerstone therapies. Similarly, Posner-Schlossman syndrome, with its elevated IOP and mild anterior chamber reaction, benefits from steroid treatment even though it may be herpetic in etiology.

The common requirements for initiating steroids are that any dendritic lesions should be reasonably healed and, if there is corneal involvement, antiviral coverage (both topical and oral) should be maintained.

Sometimes herpes simplex keratitis episodes are unresolved at seven
days. So, we frequently extend the
oral therapeutic regimen to 10 to
14 days, based on the individual
patient’s response. Systemic toxicity is not a great concern with a
conservatively longer dosage period.
Unfortunately, the drawn-out cases
are more likely to have stromal
involvement in the form of disciform
keratitis, which represents a deeper
immunologic response. Subspecialty
corneal consultation and comanagement are suggested here, as guidance
with steroid therapy and extended
periods of antiviral therapy may be
indicated.

A major breakthrough in the
treatment of herpes simplex keratitis
came from the National Eye Institute’s Herpetic Eye Disease Study
(HEDS) in 1999. Completed in
several sections, HEDS gave authoritative results for the oral treatment
and prevention of ocular herpes
simplex. HEDS I showed that topical
prednisone was helpful in treating
patients with stromal keratitis. It also
demonstrated that there is no benefit to adding oral acyclovir in stromal keratitis if the patient is
already taking topical steroids and antivirals.7

HEDS II demonstrated results that are more relevant to
the primary care optometrist. This study showed that oral
acyclovir in a prophylactic dosage of 400mg b.i.d. reduced
the rate of recurrence of any form of ocular herpes in the
following year by 41%. Further, HEDS II showed a 50%
reduction in the recurrence of severe forms of ocular herpes, such as disciform keratitis, if acyclovir is taken for a
year as described.

This data is very important to the eye practitioner
because it’s critical to initiate the preventative therapy as
a team approach with the patient’s family doctor. In our
experience, family practitioners may not have an acute
awareness of this treatment method, and should be educated on its importance and safety.

Another feature included in the HEDS II study was its
evaluation of oral acyclovir’s efficacy in preventing epithelial herpes simplex from developing into stromal disease or
iritis. The study found no added benefit to oral acyclovir if
the patient was already taking topical trifluridine.8

However, informal discussion with corneal specialists
shows that oral antiviral therapy is currently popular as
an adjunct therapy in treating epithelial disease. One could
speculate that there is doubt on the study results, or that
the oral therapy speeds resolution of the epithelial disease
itself. Further, we find that patients with signs of acute
ocular herpes may show symptoms of systemic inflammation, such as fever, and may benefit from oral treatment.

Herpes Zoster Ophthalmicus

Oral Dosing for Herpes Zoster

Oral agents for herpes zoster ophthalmicus should be administered as follows:

Zovirax (acyclovir, GlaxoSmithKline) 800mg five times daily for seven to 10 days.

Valtrex (valacylovir, GlaxoSmithKline) 1,000mg three times daily for seven to 10 days

Famvir (famciclovir, Novartis) 500mg three times daily for seven to 10 days.

Note that the Physician’s Desk Reference indicates higher oral antiviral doses for herpes zoster than for herpes simplex. This may be due to the longer duration

The herpes zoster virus is the same varicella agent that
causes chicken pox in its initial infection. As with herpes
simplex, herpes zoster has been recognized for more than
a century. Zoster’s features were elaborated by William Heberden in the late 1700s, differentiating it from the simplex virus. In
1888, Janus Von Bokay was the first
researcher to suggest that chicken
pox and shingles were caused by the
same virus.10

Because the human immune system is unable to eradicate the virus,
it remains latent in sensory ganglia
until an episode of immunologic
compromise. Activation of the zoster virus causes hyperesthesia in the
affected sensory nerves within two
to three days, with the characteristic
papillovesicular rash soon to follow.11

Fifty percent to 70% of patients
have ocular involvement if the first
division of the fifth cranial nerve is
involved.11 Viral infection and subsequent inflammation can affect all
ocular structures. Corneal scarring
and uveitis with secondary cataract,
glaucoma and macular edema are
especially worrisome possibilities. Corneal staining and mucoid plaques
may serve as signals that these serious involvements are on the way.12 Upon presentation of herpes zoster
ophthalmicus, it is critical to initiate
systemic treatment with oral antiviral
agents (see “Oral Dosing for Herpes
Zoster,” above). Research has shown
the benefit of systemic therapy if
instituted within 48 hours of vesicular outbreak.13 Beyond 72 hours,
its efficacy is diminished though it
may still be helpful. Topical antiviral
agents have not been shown to be
effective, but they are sometimes
used if there is clinical uncertainty in
considering zoster vs. simplex. For
example, it may be justified to start
topical antivirals if a patient manifests lid vesicles and early, poorly
differentiated dendrites, thus blurring
the lines between simplex and zoster.

However, potential toxicity of
topical trifluridine requires cautious
follow-up care. Follow-up on herpes zoster ophthalmicus should be
undertaken at least on alternate days
until the inflammation subsides and
the patient perceives better comfort.
Also, be sure to consult with the
patient’s family physician to rule out
any underlying immunosuppression
as a cause for the zoster outbreak. A particular challenge to the clinician: the patient who presents with
symptoms, but no signs of herpes
zoster ophthalmicus. We’ve had
several patients who presented with
malaise, tingling and pain along
the first division of the fifth cranial
nerve (i.e., discomfort radiating
from the superior ocular area to the
scalp). A low-grade blepharoconjunctivitis accompanied these symptoms, which was treated topically
with antibiotic-steroid combination.
The absence of vesicular eruption on
the scalp led to the diagnosis of herpes zoster sine herpetum, as creeping
lesions were missing despite classic
symptomatology. We started oral
Valtrex at 1,000mg three times daily
for 10 days, with confidence and
justification in the principle that
the risk of therapy well outweighed
the risk of the disease process itself.

Herpes zoster is a greater risk to
our patients as they age. As primary care doctors, we can recommend
that patients consult with their
family physicians about vaccination against this disease. Zostavax
(Merck), a herpes zoster vaccine,
has been shown to reduce herpes
zoster episodes by 51% in patients
60 to 69 years old.14 It also reduces
the chances of post-herpetic neuralgia by 67%. This vaccine is given
in the form of an attenuated live
virus, which stimulates the immune
system to fight off the herpes zoster
infection. Patients who are highly
allergic, immune compromised, or
who suffer from tuberculosis are
excluded from this new vaccine.

Simplex vs. Zoster

Viral illness, herpes simplex and
herpes zoster share some features
in common—all can cause systemic
illness and vesicular lesions, for
instance. So, it is critical to distinguish some of the subtle features. For
example, simplex tends to cause true
dendritic corneal lesions, while zoster
causes pseudodendrites or simpler
diffuse staining. Simplex can follow
multiple nerve branches, while zoster
tends to follow a single nerve branch,
such as the first division of the fifth
cranial nerve.

There are also differences in
terms of the timelines of each disease. Simplex often causes recurrently acute disease, while zoster
consequences are more chronic.15 Herpes simplex keratitis often
responds well to treatment within
a week, though repeated episodes
are common and increase the risk
of scarring. Our experience with
zoster keratitis, as well as uveitis,
is that episodes that can go on for
weeks or longer. However, recurrence is usually much less frequent.

When Things Don’t Go Well

Keratitis from both herpes simplex and herpes zoster can have
prolonged clinical courses. Their
tendency to cause corneal scarring
requires close attention, as the visual axis can be threatened rapidly by
white blood cell infiltration.

Judicious use of steroids is the
key to success, and many cases
merit consultation with a corneal
specialist. Soft steroids, such as
fluorometholone, can be started
at four to six times daily when the
corneal epithelium is reasonably
closed. Viral suppression by oral
and/or topical agents should be
maintained, because steroids suppress the eye’s ability to fight the
herpes virus.

As a rule of thumb, I seek corneal consultation if a herpetic
corneal infiltrate is anticipated to
cause a patient to lose acuity, or if
the patient shows no improvement
after several days of treatment.

Uveitis is another complication
of herpes infections that may present after the initial visit. Ensure
that the patient is taking the
maximum oral antiviral therapy
with good compliance. If uveitis appears, there can be a rapid
development of inflammation that
requires aggressive treatment. A
loading dose of topical Pred Forte
(prednisolone acetate 1%, Allergan) given every 15 minutes for
a few hours, followed by a week
of hourly dosing, is a reasonable
start. Cycloplegia with a long-acting agent, such as homatropine
5%, is necessary. As with potential
corneal scarring, seek subspecialty
consultation if herpes associated
uveitis is slow to resolve.

Herpes and Bell’s Palsy

Bell’s facial nerve palsy has been
shown to have herpes simplex
or herpes zoster as causative factors in some cases.16,17 Although controversial, many clinicians use
oral antivirals, such as acyclovir,
in addition to the standard oral
prednisone treatment.18 As facial
nerve palsy patients often present
to optometric practices, it is worth while to consult with the treating
physician regarding the possibility
of initiating antiviral therapy.

Dry eye due to exposure with
poor lid function is your main concern in these patients. Assurance of
proper systemic therapy takes the
patient’s care to a higher level.

Proper, effective care of patients
suffering from the herpes viruses
can be quite rewarding. When
complications lead to referral
for specialty care, you remain a
vital part of the health care team.
Thorough knowledge of treatment
options and keen observation will
help your patients get through
these difficult episodes.